Anticonvulsant derivatives useful in treating autism

ABSTRACT

Anticonvulsant derivatives useful in treating autism.

This application claims priority from a Provisional Application No.60/119,104 filed Feb. 8, 1999.

BACKGROUND OF THE INVENTION

Compounds of Formula I:

are structurally novel antiepileptic compounds that are highly effectiveanticonvulsants in animal tests (Maryanoff, B. E, Nortey, S. O.,Gardocki, J. F., Shank, R. P. and Dodgson, S. P. J. Med. Chem. 30,880-887, 1987; Maryanoff, B. E., Costanzo, M. J., Shank, R. P.,Schupsky, J. J., Ortegon, M. E., and Vaught J. L. Bioorganic & MedicinalChemistry Letters 3, 2653-2656, 1993). These compounds are covered byU.S. Pat. No.4,513,006. One of these compounds2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate known astopiramate has been demonstrated in clinical trials of human epilepsy tobe effective as adjunctive therapy or as monotherapy in treating simpleand complex partial seizures and secondarily generalized seizures (E.FAUGHT, B. J. WILDER, R. E. RAMSEY, R. A. REIFE, L D. KRAMER, G. W.PLEDGER, R. M. KARIM et. al., Epilepsia 36 (S4) 33, 1995; S. K. SACHDEO,R. C. SACHDEO, R. A. REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S4) 33,1995), and is currently marketed for the treatment of simple and complexpartial seizure epilepsy with or without secondary generalized seizuresin approximately twenty countries including the United States, andapplications for regulatory approval are presently pending in severaladditional countries throughout the world.

Compounds of Formula I were initially found to possess anticonvulsantactivity in the traditional maximal electroshock seizure (MES) test inmice (SHANK, R. P., GARDOCKI, J. F., VAUGHT, J. L., DAVIS, C. B.,SCHUPSKY, J. J., RAFFA, R. B., DODGSON, S. J., NORTEY, S. O., andMARYANOFF, B. E., Epilepsia 35 450-460, 1994). Subsequent studiesrevealed that Compounds of Formula I were also highly effective in theMES test in rats. More recently topiramate was found to effectivelyblock seizures in several rodent models of epilepsy (J. NAKAMURA, S.TAMU , T. KANDA, A. ISHII, K. ISHIHARA, T. SERIKAWA, J. YAMADA, and M.SASA, Eur. J. Pharmacol. 254 83-89, 1994), and in an animal model ofkindled epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24, 73-77,1996).

Clinical studies on topiramate have revealed previously unrecognizedpharmacological properties which suggest that topiramate will beeffective in treating autism

Accordingly, it has been found that compounds of the following formulaI:

wherein X is O or CH₂, and R1, R2, R3, R4 and R5 are as definedhereinafter are useful in maintaining weight loss.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The sulfamates of the invention are of the following formula (I):

wherein

X is CH₂ or oxygen;

R₁ is hydrogen or alkyl; and

R₂, R₃, R₄ and R₅ are independently hydrogen or alkyl and, when X isCH₂, R₄ and R₅ may be alkene groups joined to form a benzene ring and,when X is oxygen, R₂ and R₃ andlor R₄ and R₅ together may be amethylenedioxy group of the following formula (II):

 wherein

R₆ and R₇ are the same or different and are hydrogen, lower alkyl or arealkyl and are joined to form a cyclopentyl or cyclohexyl ring.

R₁ in particular is hydrogen or alkyl of about 1 to 4 carbons, such asmethyl, ethyl and iso-propyl. Alkyl throughout this specificationincludes straight and branched chain alkyl. Alkyl groups for R₂, R₃, R₄,R₅, R₆ and R₇ are of about 1 to 3 carbons and include methyl, ethyl,iso-propyl and n-propyl. When X is CH₂, R₄ and R₅ may combine to form abenzene ring fused to the 6-membered X-containing ring, i.e., R₄ and R₅are defined by the alkatrienyl group ═C—CH═CH—CH═.

A particular group of compounds of formula (I) is that wherein X isoxygen and both R₂ and R₃ and R₄ and R₅ together are methylenedioxygroups of the formula (II), wherein R₆ and R₇ are both hydrogen bothalkyl or combine to form a spiro cyclopentyl or cyclohexyl ring, inparticular where R₆ and R₇ are both alkyl such as methyl. A second groupof compounds is that wherein X is CH₂ and R₄ and R₅ are joined to form abenzene ring. A third group of compounds of formula (I) is that whereinboth R₂ and R₃ are hydrogen.

The compounds of formula (I) may be synthesized by the followingmethods:

(a) Reaction of an alcohol of the formula RCH₂OH with a chlorosulfamateof the formula CISO₂NH₂ or CISO₂NHR₁ in the presence of a base such aspotassium a-butoxide or sodium hydride at a temperature of about −20° to25° C. and in a solvent such as toluene, THF or dimethylformamidewherein R is a moiety of the following formula (III):

(b) Reaction of an alcohol of the formula RCH₂OH with sulfurylchlorideof the formula SO₂Cl₂ in the presence of a base such as triethylamine orpyridine at a temperature of about −40° to 25° C. in a solvent such asdiethyl ether or methylene chloride to produce a chlorosulfate of theformula RCH₂OSO₂Cl.

The chlorosulfate of the formula RCH₂OSO₂Cl may then be reacted with anamine of the formula R₁NH₂ at a temperature of abut 40° to 25° C. in asolvent such as methylene chloride or acetonitrile to produce a compoundof formula (I). The reaction conditions for (b) are also described by T.Tsuchiya et al. in Tet. Letters, No. 36, p. 3365 to 3368 (1978).

(c) Reaction of the chlorosulfate RCH₂OSO₂Cl with a metal azide such assodium azide in a solvent such as methylene chloride or acetonitrileyields an azidosulfate of the formula RCH₂OSO₂N₃ as described by M.Hedayatullah in Tet. Lett. p. 2455-2458 (1975). The azidosulfate is thenreduced to a compound of formula (I) wherein R₁ is hydrogen by catalytichydrogenation, e.g. with a noble metal and H₂ or by heating with coppermetal in a solvent such as methanol.

The starting materials of the formula RCH₂OH may be obtainedcommercially or as known in the art. For example, starting materials ofthe formula RCH₂OH wherein both R₂ and R₃ and R₄ and R₅ are identicaland are of the formula (II) may be obtained by the method of R. F. Bradyin Carbohydrate Research, Vol. 14, p. 35 to 40 (1970) or by reaction ofthe trimethylsilyl enol ether of a R₆COR₇ ketone or aldehyde withfructose at a temperature of about 25° C., in a solvent such ahalocarbon, e.g. methylene chloride in the presence of a protic acidsuch as hydrochloric acid or a Lewis Acid such as zinc chloride. Thetrimethylsilyl enol ether reaction is described by G. L. Larson et al inJ. Org. Chem. Volaa 38, No. 22, p. 3935 (1973).

Further, carboxylic acids and aldehydes of the formulae RCOOH and RCHOmay be reduced to compounds of the formula RCH2OH by standard reductiontechniques, e.g. reaction with lithium aluminum hydride, sodiumborohydride or borane-THF complex in an inert solvent such a diglyme,THF or toluene at a temperature of about 0° to 100° C., e.g. asdescribed by H. O. House in “Modern Synthetic Reactions”, 2nd Ed., pages45 to 144 (1972).

The compounds of formula I: may also be made by the process disclosed inU.S. Pat. No. 5,387,700, which is incorporated by reference herein.

The compounds of formula I include the various individual isomers aswell as the racemates thereof, e.g., the various alpha and betaattachments, i.e., below and above the plane of the drawing, of R₂, R₃,R₄ and R₅ on the 6-membered ring. Preferably, the oxygene of themethylenedioxy group (II) are attached on the same side of the6-membered ring.

Autism is observed in a group of disorders called the pervasivedevelopmental disorders (e.g., Autistic Disorder, Rett's Disorder,Asperger's Disorder, Pervasive Developmental Disorder Not OtherwiseSpecified (Including Atypical Autism). Such disorders are behaviorallydefined disorders featuring qualitative impaired social interaction,language, communication and range of interests and activities. As usedherein “autism” is used to cover all such disorders. Perseveration,stereotypy, concreteness, affective blunting, failure to develop peerrelationships appropriate to developmental level and lack of insightinto other person's thinking may be conspicuous along with motorstereotypies. In a proportion of cases, autism is associated withepilepsy, (eg., conditions such as a paroxysmal EEG or even statusepilepticus in slow wave sleep). Beaumanoir A, Bureau M, Deonna T, etal. Eds. Continuous spikes and waves during slow wave sleep-electricalstatus epilepticus during slow wave sleep-Acquired epileptic aphasia andrelated conditions. John Libbey, 1995. Autistic regression also overlapswith acquired epileptic aphasia (Landau-Kleffner Syndrome). Landau W M,Kleffner F R. Syndrome of Acquired Aphasia with convulsive disorder inchildren. Neurology 1957; 523-530. Therefore, the treatment ofunderlying seizure disorder has a direct relationship to the treatmentof autism.

Abnormal plasma levels of glutamate may be found in some autisticchildren Moreno-Fuenmayor H. Borjas L. Arrieta A. Valera V.Socorro-Candanoza L. Plasma excitatory amino acids in autism.Investigacion Clinica.37(2): 113-28, June 1996. Genes for the threeGABA_(A) receptor subunits on chromosome 15q have been shown to haveaberrations in autism Schroer R J, Phelan M C, Michaelis R C, Crawford EC, Skinner S A, Cuccaro M, Simensen R J, Bishop J, Skinner C, Fender D,Stevensen R E. Autism and mathematically derived aberrations ofchromosome 15q. American Journal of Medical Genetics. 76(4): 327-36,Apr. 1, 1998. There are also serotonin abnormalities in autism (Cook EH. Leventhal B L. The serotonin system in autism. Current Opinion inPediatrics.8(4):348-354, August 1996), which will be treated throughGABA and glutamate alterations induced by compounds of formula I.

Placebo controlled, add on trials of topiramate in adults and childrenwith partial onset seizures have shown a statistically significantreduction of seizure rate greater for Topiramate than placebo. There isalso known enhancement of GABA activity in the brain along with reducedglutamate receptor activity. Accordingly, compounds of formula I areuseful in the treatment of autism.

For treating autism, a compound of formula (I) may be employed at adaily dosage in the range of about 50 to 600 mg, usually in two divideddoses, for an average adult human. A unit dose would contain about 25 to200 mg of the active ingredient.

To prepare the pharmaceutical compositions of this invention, one ormore sulfamate compounds of formula (I) are intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration, e.g.,oral, by suppository, or parenteral. In preparing the compositions inoral dosage form, any of the usual pharmaceutical media may be employed.Thus, for liquid oral preparations, such as for example, suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents and the like; for solid oral preparations such as, for example,powders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. Suppositories may be prepared, in whichcase cocoa butter could be used as the carrier. For parenterals, thecarrier will usually comprise sterile water, though other ingredients,for example, for purposes such as aiding solubility or for preservation,may be included. Injectable solutions may also be prepared in which caseappropriate stabilizing agents may be employed. Topiramate is currentlyavailable for oral administration in round tablets containing 25 mg, 100mg or 200 mg of active agent. The tablets contain the following inactiveingredients: lactose hydrous, pregelatinized starch, microcrystallinecellulose, sodium starch glycolate, magnesium stearate, purified water,camauba wax, hydroxypropyl methylcellulose, titanium dioxide,polyethylene glycol, synthetic iron oxide, and polysorbate 80.

The pharmaceutical compositions herein will contain, per dosage unit,e.g., tablet, capsule, powder injection, teaspoonful, suppository andthe like from about 25 to about 200 mg of the active ingredient.

What is claimed is:
 1. A method for treating an individual exhibitingone or more of the symptoms of autism in mammals comprisingadministering to such a mammal a therapeutically effective amount fortreating such condition of a compound of Formula I:

wherein X is CH₂ or oxygen; R₁ is hydrogen or alkyl; and R₂, R₃, R₄ andR₅ are independently hydrogen or alkyl and, when X is CH₂, R₄ and R₅,may be alkene groups joined to form a benzene ring and, when X isoxygen, R₂ and R₃ and/or R₄ and R₅ together may be a methylenedioxygroup of the following formula(II):

 wherein R₆ and R₇ are the same or different and are hydrogen, or alkyland are joined to form a cyclopentyl or cyclohexyl ring.
 2. The methodof claim 1 wherein the compound of formula I is topiramate.
 3. Themethod of claim 1, wherein the therapeutically effective amount is offrom about 50 to 600 mg/day.
 4. The method of claim 1, wherein theamount is of from about 25 to 200 mg/day.